Gymnastics participation is associated with skeletal benefits in the distal forearm: a 6-month study using peripheral Quantitative Computed Tomography.

OBJECTIVES: Musculoskeletal development of the upper limbs during exposure to weight-bearing loading is under-researched during early pubescent growth. The purpose was to assess the changes in upper body musculoskeletal strength in young girls following 6 months of non-elite gymnastics participation. METHODS: Eighty-four girls, 6-12 years were divided into groups based on gymnastics participation: high-training (HGYM, 6-16 hr/wk), low-training (LGYM, 1-5 hr/wk), and non-gymnasts (NONGYM). Volumetric BMD, bone geometry, estimated bone strength and muscle size were assessed at the non-dominant forearm (4% and 66% radius and ulna) with pQCT. DXA assessed aBMD and body composition. Tests for explosive power, muscle strength, and endurance were also performed. RESULTS: Interaction effects were observed in all variables at the 4% radius. At the 66% ulna, HGYM and LGYM had greater bone mass, size and bone strength than NONGYM, furthermore a dose-response relationship was observed at this location. Body composition was better for HGYM than LGYM and NONGYM, however muscle function was better for HGYM and LGYM than NONGYM. CONCLUSION: The greatest changes were obtained with more than one gymnastics class per week. Separating gymnastics participation-related changes from those associated with normal growth and development remains difficult, particularly at the 4% radius.

Bone health of apprentice jockeys using peripheral quantitative computed tomography.

Our aim was to use Peripheral Quantitative Computed Tomography (pQCT) to assess the bone health of male and female apprentice jockeys and age- and sex-matched peers. 2 groups of 25 young adults (n=50) (age range 15-38 years) were comprised of male and female apprentice jockeys, and male and female controls. We used pQCT to measure the distal tibia and distal radius. After covarying for weight and limb length, apprentice jockeys displayed less tibial cortical area and lower strength strain index at 14% distal shaft, 38% mid shaft and 66% proximal sites measured distally than controls (p=0.001). No between group differences were found in cortical density, trabecular area, and trabecular density at the tibia. Compared with controls, apprentice jockeys displayed greater trabecular density at the distal radial site (p=0.001), greater strength strain index at 66% proximal site measured distally (p=0.01), and a lower strength strain index at the distal radius (p=0.006). In conclusion, only trabecular density at the distal radius and strength strain index at the proximal radius were greater in apprentice jockeys than controls. Strategies to increase bone density and bone strength in apprentice jockeys should be considered by relevant industry stakeholders and their health providers.

Non-elite gymnastics participation is associated with greater bone strength, muscle size, and function in pre- and early pubertal girls.

UNLABELLED: Recent reports indicate an increase in forearm fractures in children. Bone geometric properties are an important determinant of bone strength and therefore fracture risk. Participation in non-elite gymnastics appears to contribute to improving young girls' musculoskeletal health, more specifically in the upper body. INTRODUCTION: The primary aim of this study was to determine the association between non-elite gymnastics participation and upper limb bone mass, geometry, and strength in addition to muscle size and function in young girls. METHODS: Eighty-eight pre- and early pubertal girls (30 high-training gymnasts [HGYM, 6-16 hr/ wk], 29 low-training gymnasts [LGYM, 1-5 h r/wk] and 29 non-gymnasts [NONGYM]), aged 6-11 years were recruited. Upper limb lean mass, BMD and BMC were derived from a whole body DXA scan. Forearm volumetric BMD, bone geometry, estimated strength, and muscle CSA were determined using peripheral QCT. Upper body muscle function was investigated with muscle strength, explosive power, and muscle endurance tasks. RESULTS: HGYM showed greater forearm bone strength compared with NGYM, as well as greater arm lean mass, BMC, and muscle function (+5% to +103%, p < 0.05). LGYM displayed greater arm lean mass, BMC, muscle power, and endurance than NGYM (+4% to +46%, p < 0.05); however, the difference in bone strength did not reach significance. Estimated fracture risk at the distal radius, which accounted for body weight, was lower in both groups of gymnasts. Compared with NONGYM, HGYM tended to show larger skeletal differences than LGYM; yet, the two groups of gymnasts only differed for arm lean mass and muscle CSA. CONCLUSION: Non-elite gymnastics participation was associated with musculoskeletal benefits in upper limb bone geometry, strength and muscle function. Differences between the two gymnastic groups emerged for arm lean mass and muscle CSA, but not for bone strength.

Skeletal differences at the ulna and radius between pre-pubertal non-elite female gymnasts and non-gymnasts.

OBJECTIVE: To compare skeletal parameters between the ulna and radius in pre-pubertal non-elite gymnasts and non-gymnasts. METHODS: Fifty-eight non-elite artistic gymnasts, aged 6-11 years, were compared with 28 non-gymnasts for bone mineral content (BMC), total and cortical bone area (ToA, CoA), trabecular and cortical volumetric density (TrD, CoD) and estimated bone strength (BSI and SSIp), obtained by pQCT at the distal and proximal forearm. RESULTS: Gymnasts had greater estimated bone strength than non-gymnasts at both sites of the forearm. At the distal forearm, the gymnastics-induced skeletal benefits were greater at the radius than ulna (Z-scores for BMC, TrD and BSI +0.40 to +0.61 SD, p<0.05 vs. +0.15 to +0.48 SD, NS). At the proximal forearm, the skeletal benefits were greater at the ulna than the radius (Z-scores for BMC, ToA, CoA and SSIp +0.59 to +0.82 SD, p<0.01 vs. +0.35 (ToA) and +0.43 SD (SSIp), p<0.01). CONCLUSION: Skeletal benefits at the distal and proximal forearm emerged in young non-elite gymnasts. Benefits were larger when considering skeletal parameters at both the ulna and radius, than the radius alone as traditionally performed with pQCT. These findings suggest the ulna is worth investigating in future studies aiming to accurately quantify exercise-induced skeletal adaptations.

Calcium and vitamin-D supplementation on bone structural properties in peripubertal female identical twins: a randomised controlled trial.

UNLABELLED: A randomised controlled trial was used in assessing the impact of 6 months of daily calcium and vitamin-D supplementation on trabecular and cortical bone acquisition at distal tibial and radial sites using peripheral quantitative computed tomography (pQCT). Daily supplementation was associated with increased bone density and bone strength at the distal tibia and radius. INTRODUCTION: pQCT has not been used to assess bone responses to calcium and vitamin-D supplementation on peripubertal children. This randomised controlled trial aimed to assess the impact of a 6-month daily calcium and vitamin-D supplementation on trabecular and cortical bone acquisition at distal tibial and radial sites using pQCT. METHODS: Twenty pairs of peripubertal female identical twins, aged 9 to 13 years, were randomly assigned to receive either 800 mg of calcium and 400 IU of vitamin D3, or a matched placebo. Bone structural properties at the distal tibia and distal radius were acquired at baseline and 6 months. RESULTS: The calcium-supplemented group showed greater gains in trabecular density, trabecular area and strength strain index at the 4% of distal tibial and radial sites compared with the placebo group (p=0.001). Greater gains in cortical area at the 38% and 66% of tibial sites were also found in twins receiving the calcium supplement (p=0.001). CONCLUSIONS: Daily supplementation for a period of 6 months was associated with increased trabecular area, trabecular density and strength strain index at the ultra-distal tibia and radius and increased cortical area at tibial mid-shaft.

Assessment of bone strength at differentially-loaded skeletal regions in adolescent middle-distance runners.

Bone adaptations to loading extend beyond mineral accrual to geometric markers of bone strength. Available technology and regional differences in cortical bone dictate how bone strength is reported. Examination of bone strength at two differentially-loaded skeletal sites using hip structure analysis (HSA) and bone strength index (BSI) is under-explored in adolescent sporting populations. The purpose of this study was to compare HSA at the femoral neck and BSI at the distal tibia in adolescent middle-distance runners and age- and gender-matched controls. Four groups of 20 adolescents aged 14-18 years were composed of male and female middle-distance runners, and male and female controls. Distal tibial BSI was calculated using data from dual energy X-ray absorptiometry (DXA) and magnetic resonance imaging (MRI). Calculations for femoral neck strength were acquired from DXA-derived HSA software. Female athletes displayed greater distal tibial BSI than controls t(38)=3.4, p=0.002, but femoral neck bone measures did not differ. In males, no group differences were found at either the distal tibia or femoral neck. In conclusion, exposure to similar high training loads may advantage female adolescent athletes more than male adolescent athletes compared with less active peers in bone strength at the distal tibia.

A challenge to fitness testing in primary schools.

We challenge the tradition of fitness testing in schools on the basis of purpose, procedures and outcomes. A number of assumptions about validity of selected tests are raised. The need to be able to track fitness through childhood into adulthood is challenged with limited scientific evidence of longitudinal tracking. Supporters of wide-scale fitness testing of children in schools include researchers whose intention is to promote public health awareness and policy. But a variety of confounding factors can affect field-based testing and lower the confidence in intra and inter group comparisons. Confounders include variability in motivation, familiarisation, external conditions, group dynamics, self-efficacy in testing, and perceived value of testing and likely outcomes. With acknowledged limitations, a more appropriate context for fitness testing for young people who have a strong commitment to physical activity may lie more in a professionally delivered sports-specific setting rather than in large-scale school-based testing. Given the less than desirable participation in activity outside of school and the distressing prevalence of childhood overweight and obesity, it is unlikely that fitness testing experiences will provide children with much needed positive encouragement for lifelong physical activity. Alternative strategies for school-based assessment of the promotion of child health through physical activity are proposed.

Bone strength index in adolescent girls: does physical activity make a difference?

BACKGROUND: Bone strength index (BSI) combines bone mineral and bone biomechanical properties to measure resistance to bending. This index may have greater clinical significance than the more often described markers of bone mineral content (BMC), areal density, or geometry alone and, in turn, may show a stronger relation to fracture risk. The BSI is the product of volumetric cortical bone mineral density (BMD) and cross sectional moment of inertia within a region of interest. Calculations combine dual energy x ray absorptiometry and magnetic resonance imaging technologies and provide a useful, non-invasive measure of in vivo bone strength. OBJECTIVES: (a) To compare BSI in adolescent female middle distance runners and age matched controls; (b) to examine factors predictive of BSI in adolescent girls. METHODS: Twenty adolescent female middle distance runners (mean (SD) age 16 (1.7) years, physical activity 8.9 (2.1) hours a week) and 20 female controls (age 16 (1.8) years, physical activity 2.0 (0.07) hours a week) were recruited. To calculate BSI, a region of interest representing 10% of the mid-distal tibia was analysed for dual energy x ray absorptiometry derived BMC and was combined with bone geometry and biomechanical properties obtained by magnetic resonance imaging assessments. Potential predictors of BSI were also examined. RESULTS: Independent t tests showed that BMC (p = 0.028), cortical bone volume (p = 0.002), volumetric cortical BMD (p = 0.004), cross sectional moments of inertia (p = 0.005), and BSI (p = 0.002) were higher in the distal tibia of athletes than of controls. The strongest predictor of BSI was hours of physical activity a week (R2 = 0.46). CONCLUSIONS: Athletes habitually exposed to high training loads displayed greater BSI at the distal tibia than controls. The results further confirm BSI as a significant and discerning marker in musculoskeletal health in adolescent girls engaged in high and low mechanical loading.

Musculoskeletal health in elite male adolescent middle-distance runners.

The impact of high training volumes on musculoskeletal adaptations of male adolescents is poorly understood. We compared bone mineral content (BMC) of total body, lumbar spine and proximal femur using Dual X-ray Absorptiometry (Lunar Prodigy, GE Medical Systems, Madison WI) in elite level (n=20), male adolescent middle distance runners (mean 16.8 yrs, range 14-18 yrs) and age-matched (n=20) controls. Athletes averaged 14 hrs of physical activity per week and controls reported participating in physical activity an average of two hrs per week. Total body mass was 10.97 kg less in athletes than controls (p=0.005). Within the total body mass difference, fat tissue mass of athletes was 10.93 kg less in athletes than controls (p= 0.001). Multiple regression analysis identified total body lean mass and total body fat mass as the strongest predictors of total body BMC (R2 0.71). After adjusting for lean tissue mass per kg of body weight (p=0.07), no difference in BMC was detected. Lower limb muscle strength and macronutrient intakes were also measured but no between group differences were found. The number of weeks of training and/or competition missed through injury was not associated with total body BMC (R2=0.19) among athletes. Our results imply high training volumes in middle distance running are not detrimental to musculoskeletal health and are associated with positive body composition profiles in elite adolescent male athletes.

Digital electron microscopic examination of human sural nerve biopsies.

Diabetic peripheral polyneuropathy is characterized by axonal degeneration and regeneration as well as by Schwann cell and microvascular changes. These changes have been described at both the light (LM) and the electron microscopic (EM) levels; however, EM has not been applied to large clinical trials. Our goal was to adapt the rigorous techniques used for quantifying human biopsies with LM image analysis to accommodate ultrastructural analyses. We applied digital image capture and analysis to the ultrastructural examination of axons in sural nerve biopsies from diabetic patients enrolled in a multicenter clinical trial. The selection of sural nerve biopsies was based on the quality of specimen fixation, absence of physical distortion, and nerve fascicle size (> or =100,000; < or =425,000 microm2). Thin sections were collected on formvar-coated slot grids, stabilized with carbon and scanned on a Phillips CM100 transmission electron microscope. Digital images were captured with a Kodak Megaplus 1.6 camera. A montage was constructed using software derived from aerial mapping applications, and this virtual image was viewed by EM readers. Computer-assisted analyses included identification and labeling of individual axons and axons within regenerating clusters. The average density of regenerating myelinated axon clusters per mm2 was 65.8 +/- 5.1, range of 0-412 (n = 193). These techniques increase the number of samples that may be analyzed by EM and extend the use of this technique to clinical trials using tissue biopsies as a primary endpoint.

Glycemic control is related to the morphological severity of diabetic sensorimotor polyneuropathy.

OBJECTIVE: The aim of the current study was to determine the independent clinical risk factors for predicting morphological severity of distal diabetic sensorimotor polynecuropathy (DSP) as determined by fiber density (FD) on sural nerve biopsy. RESEARCH DESIGN AND METHODS: A total of 89 patients with both type 1 and type 2 diabetes, ascertained from a large therapeutic randomized clinical trial, were included in this observational cohort study. Morphological severity of DSP was expressed as the myelinated FD in the sural nerve biopsy General linear models were used to assess the relationship between the morphological severity of DSP and various clinical risk factors. RESULTS: Glycated hemoglobin (GHb) was significantly related to FD in univariate and multivariate regression analyses. This relationship was present in models in which GHb was handled either as a continuous variable or as a categorical variable with the highest significance level, with a GHb cutoff level of 9%. After dividing patients into groups with optimal to moderate GHb < or = 9%) and suboptimal (GHb >9%) glycemic control, the difference in FD between the two groups ranged between 3,461 and 2,334 per mm2. FD was also significantly related to duration of diabetes and age of the patient. CONCLUSIONS: The severity of peripheral DSP expressed by morphological criteria was significantly related to glycemic control in type 1 and type 2 diabetic patients. Inconsistent with previously published electrophysiological data demonstrating a correlation between height and conduction velocity, increasing height is not associated with morphological severity. Based on the results of the present study, it might be hypothesized that improving glycemic control will lessen severity of DSP in terms of FD loss in subjects with diabetes.

Evaluation of alpha(1)-adrenoceptor antagonist on diabetes-induced changes in peripheral nerve function, metabolism, and antioxidative defense.

The role for nerve blood flow (NBF) vs. other factors in motor nerve conduction (MNC) slowing in short-term diabetes was assessed by evaluating alpha(1)-adrenoceptor antagonist prazosin on NBF, MNC, as well as metabolic imbalances and oxidative stress in the neural tissue. Control and diabetic rats were treated with or without prazosin (5 mg.kg(-1).d(-1) for 3 wk). NBF was measured by hydrogen clearance. Both endoneurial vascular conductance and MNC velocity were decreased in diabetic rats vs. controls, and this decrease was prevented by prazosin. Free NAD(+):NADH ratios in mitochondrial cristae, matrix, and cytosol assessed by metabolite indicator method, as well as phosphocreatine levels and phosphocreatine/creatine ratios, were decreased in diabetic rats, and this reduction was ameliorated by prazosin. Neither diabetes-induced accumulation of two major glycation agents, glucose and fructose, as well as sorbitol and total malondialdehyde plus 4-hydroxyalkenals nor depletion of myo-inositol, GSH, and taurine or decrease in (Na/K)-ATP-ase activity were affected by prazosin. In conclusion, decreased NBF, but not metabolic imbalances or oxidative stress in the neural tissue, is a key mechanism of MNC slowing in short-term diabetes. Further experiments are needed to estimate whether preservation of NBF is sufficient for prevention of nerve dysfunction and morphological abnormalities in long-standing diabetes or whether the aforementioned metabolic imbalances closely associated with impaired neurotropism are of greater importance in advanced than in early diabetic neuropathy.

Effects of DL-alpha-lipoic acid on peripheral nerve conduction, blood flow, energy metabolism, and oxidative stress in experimental diabetic neuropathy.

Experimental diabetic peripheral neuropathy (DPN) is marked by impaired nerve conduction velocity (NCV), reduced nerve blood flow (NBF), and a variety of metabolic abnormalities in peripheral nerve that have been variously ascribed to hyperglycemia, abnormal fatty acid metabolism, ischemic hypoxia, and/or oxidative stress. Some investigators propose that NCV slowing in experimental DPN can be explained entirely on the basis of nerve energy depletion secondary to reduced NBF. This article reports highly selective effects of administration of the antioxidant DL-alpha-lipoic acid (LA) to streptozotocin-injected diabetic rats. LA improved digital sensory but not sciatic-tibial motor NCV, corrected endoneurial nutritive but not composite NBF, increased the mitochondrial oxidative state without correcting nerve energy depletion, and enhanced the accumulation of polyol pathway intermediates without worsening myo-inositol or taurine depletion. These studies implicate oxidative stress as an important pathophysiological factor in experimental DPN. They reveal complex interrelationships among nerve perfusion, energy metabolism, osmolyte content, conduction velocity, and oxidative stress that may reflect the heterogeneous and compartmentalized composition of peripheral nerve.

Early changes in lipid peroxidation and antioxidative defense in diabetic rat retina: effect of DL-alpha-lipoic acid.

This study was designed to (1) evaluate retinal lipid peroxidation in early diabetes by the method specific for free malondialdehyde and 4-hydroxyalkenals, (2) identify impaired antioxidative defense mechanisms and (3) assess if enhanced retinal oxidative stress in diabetes is prevented by the potent antioxidant, DL-alpha-lipoic acid. The groups included control and streptozotocin-diabetic rats treated with or without DL-alpha-lipoic acid (100 mg kg(-1) day(-1), i.p., for 6 weeks). All parameters were measured in individual retinae. 4-Hydroxyalkenal concentration was increased in diabetic rats (2.63+/-0.60 vs. 1.44+/-0.30 nmol/mg soluble protein in controls, P<0.01), and this increase was prevented by DL-alpha-lipoic acid (1.20+/-0.88, P<0.01 vs. untreated diabetic group). Malondialdehyde, reduced glutathione (GSH) and oxidized glutathione (GSSG) concentrations were similar among the groups. Superoxide dismutase, glutathione peroxidase (GSHPx), glutathione reductase (GSSGRed) and glutathione transferase (GSHTrans) activities were decreased in diabetic rats vs. controls. Quinone reductase was upregulated in diabetic rats, whereas catalase and cytoplasmic NADH oxidase activities were unchanged. DL-alpha-Lipoic acid prevented changes in superoxide dismutase and quinone reductase activities induced by diabetes without affecting the enzymes of glutathione metabolism. In conclusion, accumulation of 4-hydroxyalkenals is an early marker of oxidative stress in the diabetic retina. Increased lipid peroxidation occurs in the absence of GSH depletion, and is prevented by DL-alpha-lipoic acid.

Sorbitol and myo-inositol levels and morphology of sural nerve in relation to peripheral nerve function and clinical neuropathy in men with diabetic, impaired, and normal glucose tolerance.

AIMS: Sorbitol and myo-inositol levels and morphology of sural nerve were compared with nerve function and clinical neuropathy in men with diabetic, impaired (IGT), and normal glucose tolerance. METHODS: After neurography of sural nerve and determinations of sensory thresholds for vibration, warm and cold on the foot, whole nerve sural nerve biopsy was performed in 10 men with Type 1 diabetes mellitus, 10 with IGT, and 10 with normal glucose tolerance. Polyol levels were assessed by gas-liquid chromatography/mass spectrometry. RESULTS: Sural nerve amplitudes were significantly lower and sorbitol levels significantly higher in diabetic patients (median (interquartile range)) (3.7 (3.5) microV and 643 (412) pmol/mg protein, respectively) both compared with IGT (11.3 (10.6)microV; P = 0.04 and 286 (83) pmol/mg protein; P = 0.0032, respectively) and normally glucose tolerant (10.0 (11.6); P = 0.0142 and 296 (250) pmol/mg protein; P = 0.0191, respectively) subjects. There were no differences in nerve morphology between the three groups. Nerve myo-inositol levels correlated, however, positively with cluster density (rs = 0.56; P = 0.0054). In diabetic and IGT subjects, sural nerve amplitudes (2.6 (3.8) vs. 12.1 (10.6) microV; P = 0.0246) and myelinated nerve fibre density (MNFD; 4,076 (1091) vs. 5,219 (668) nerve fibres/mm2; P = 0.0021) were significantly lower in nine subjects with clinical neuropathy than in 10 without. CONCLUSIONS: Nerve degeneration (i.e. MNFD) correlated with clinical neuropathy but not with glucose tolerance status whereas nerve myo-inositol levels positively correlated with signs of nerve regeneration (i.e. increased cluster density).

Evaluation of a sorbitol dehydrogenase inhibitor on diabetic peripheral nerve metabolism: a prevention study.

AIMS/HYPOTHESIS: Studies of the role of sorbitol dehydrogenase in nerve functional deficits induced by diabetes reported contradictory results. We evaluated whether sorbitol dehydrogenase inhibition reduces metabolic abnormalities and enhances oxidative stress characteristic of experimental diabetic neuropathy. METHODS: Control and streptozotocin-diabetic rats were treated with or without sorbitol dehydrogenase inhibitor (SDI)-157 (100 mg x kg(-1) x day(-1), in the drinking water, for 3 weeks). Sciatic nerve free mitochondrial (cristae and matrix) and cytosolic NAD(+): NADH ratios were calculated from the beta-hydroxybutyrate, glutamate and lactate dehydrogenase systems. Concentrations of metabolites, e. g. sorbitol pathway intermediates and variables of energy state were measured in individual nerves spectrofluorometrically by enzymatic procedures. RESULTS: The flux through sorbitol dehydrogenase (manifested by nerve fructose concentrations) was inhibited by 53 % and 74 % in control and diabetic rats treated with SDI compared with untreated control and diabetic groups. Free NAD(+):NADH ratios in mitochondrial cristae, matrix and cytosol were decreased in diabetic rats compared with controls and reduction in either of the three variables was not prevented by sorbitol dehydrogenase inhibitor. Phosphocreatine concentrations and phosphocreatine:creatine ratios were decreased in diabetic rats compared with controls and were further reduced by the inhibitor. Malondialdehyde plus 4-hydroxyalkenals concentration was increased and reduced gluthathione concentration was reduced in diabetic rats compared with the control group, and changes in both variables were further exacerbated by sorbitol dehydrogenase inhibitor. Neither NAD-redox and energy states nor lipid aldehyde and reduced gluthathione concentrations were affected by treatment with the inhibitor in control rats. CONCLUSION/INTERPRETATION: Inhibition of sorbitol dehydrogenase does not offer an effective approach for prevention of oxidation and metabolic imbalances in the peripheral nerve that is induced by diabetes and is adverse rather than beneficial. [Diabetologia (1999) 42: 1187-1194]

Glucose-induced oxidative stress and programmed cell death in diabetic neuropathy.

The Diabetes Control and Complications Trial (DCCT) established the importance of hyperglyemia and other consequences of insulin deficiency in the pathogenesis of diabetic neuropathy, but the precise mechanisms by which metabolic alterations produce peripheral nerve fiber damage and loss remain unclear. Emerging data from human and animal studies suggest that glucose-derived oxidative stress may play a central role, linking together many of the other currently invoked pathogenetic mechanisms such as the aldose reductase and glycation pathways, vascular dysfunction, and impaired neurotrophic support. These relationships suggest combinations of pharmacological interventions that may synergistically protect the peripheral nervous system (PNS) against the metabolic derangements of diabetes mellitus.

Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Zenarestat Study Group.

OBJECTIVE: To determine whether the aldose reductase inhibitor (ARI) zenarestat improves nerve conduction velocity (NCV) and nerve morphology in diabetic peripheral polyneuropathy (DPN). METHODS: A 52-week, randomized, placebo-controlled, double-blinded, multiple-dose, clinical trial with the ARI zenarestat was conducted in patients with mild to moderate DPN. NCV was measured at baseline and study end. Contralateral sural nerve biopsies were obtained at 6 weeks and at the study's end for nerve sorbitol measurement and computer-assisted light morphometry to determine myelinated nerve fiber density (number of fibers/mm2 cross-sectional area) in serial bilateral sural nerve biopsies. RESULTS: Dose-dependent increments in sural nerve zenarestat level and sorbitol suppression were accompanied by significant improvement in NCV. In a secondary analysis, zenarestat doses producing >80% sorbitol suppression were associated with a significant increase in the density of small-diameter (<5 microm) sural nerve myelinated fibers. CONCLUSIONS: Aldose reductase pathway inhibition improves NCV slowing and small myelinated nerve fiber loss in DPN in humans, but >80% suppression of nerve sorbitol content is required. Thus, even low residual levels of aldose reductase activity may be neurotoxic in diabetes, and potent ARIs such as zenarestat may be required to stop or reverse progression of DPN.